Tumor angiogenesis is one of the essential steps that is required for the growth and metastasis of solid tumors in human. Angiogenesis or neovascularization is the process of generating new capillary of blood vessels derived as extensions from an existing vasculature. The cells that are primarily involved in the process of angiogenesis are endothelial cells that proliferate and organize to form new blood vessels. To achieve the new blood vessel formation, endothelial cells must first escape from their stable location by breaking through the basement membrane, and this degradation is associated with migration of endothelial cells out of the vascular channel toward the angiogenic stimulus. During this process, the sub-endothelial basement membrane, a dense meshwork of collagen, glycoproteins, and proteoglycans, is proteolytically disrupted to allow formation of new capillaries. Though it is an integral component of normal processes such as reproduction and wound healing, it is known to play an important role in other pathological processes ranging from tumor growth, metastasis to inflammation, and ocular diseases.
The angiogenesis process is strongly supported by one of an important series of endothelial cell mitogens called VEGF. The vascular endothelial growth factors (VEGF) play a crucial role in neovascularization of solid tumors. The expression of VEGF has been shown to correlate with the density of micro vessels in various tumors and exhibit higher metastatic ability. Several members of the VEGF family (i.e., A, B, C, and D) and several VEGF receptors: VEGF receptor-1 (known also as Flt-1, fms-like tyrosine kinase 1), VEGF receptor-2 known as Flk-1/KDR (fetal liver kinase-1/kinase insert domain containing receptor) and VEGF receptor-3 (known as Flt-4) have been identified. All of them have seven immunoglobulin homology domains in their extracellular part and an intracellular tyrosine kinase signaling domain split by a kinase insert. By binding to one or more of these receptors, VEGF induces angiogenesis as well as permeabilization of blood vessels and thereby plays a central role in the regulation of vasculogenesis. Recently, it has been demonstrated that the extra cellular domain of VEGFR1 has an important role in vasculogenesis and angiogenesis by fixing the ligand-binding domain to the cell membrane and directly regulating the levels of ligands near the cell surface.
Due to the paramount importance of angiogenesis in the control of tumor growth, it was envisioned that the development of anti-angiogenic drugs will potentially lead to novel therapies against all types of cancers. At present, two approaches are available to inhibit VEGFR activity for use in clinical practice: therapeutic monoclonal antibodies (mAbs) target the extracellular region to block dimerization and small-molecule agents block the kinase activity that is required for VEGFR—mediated signal transduction. For example, Genentech has developed an anti-VEGF antibody that has antiangiogenic and antitumorigenic effects in animal models. So far some success has been achieved through this approach in clinical trials of patients with colorectal cancer. Also, small molecules targeted to the kinase domain have shown some success in the clinic. Sugen's SU5416 and SU 6668, Astra-Zeneca's ZD4190, and Novartis' PTK787/ZK2284 are compounds that belong to this category and some are presently being tested in clinical trials. More recently, novel low molecular weight VEGFR antagonists, 5-{3-[4-(octadecyloxy) phenyl]propionylamino}-2,4′-oxydibenzoic acid (VGA1102) and 5-[N-methyl-N-(4-octadecyloxyphenyl)acetyl]amino-2-ethylthiobenzoic acid (VGA1155) that prevent angiogenesis by binding to both VEGF receptor 1 (fms-like tyrosine kinase-1 expressing NIH3T3-cells) and VEGF receptor 2 (KDR/flk-1; VEGF receptor 2 transfected) cells at μM range have been reported. VGA1102 and VGA1155 (VGA compounds) appear to be a very specific inhibitors for VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1). These compounds do not inhibit the binding of other ligands to their receptors, such as EGF, PDGF, IL-8, PAF, IL-1b, IL-2, IL-4, IL-6, MIPs, TNF-a, and insulin.
Therefore, efficacious and specific inhibitors of VEGFR are needed as potentially valuable therapeutic agents for the treatment of cancer. It is thus desirable to discover new VEGFR inhibitors.